Exogenous Ketones for Obesity

Overseen By Sarah Purcell, PhD

Age: 18 - 65

Sex: Any

Trial Phase: Academic

Sponsor: University of British Columbia

Must not be taking: Appetite suppressants, Sleep aids

Disqualifiers: Cardiovascular, Diabetes, Cancer, Thyroid, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Approved in 2 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 3

22 Participants Needed

Trial Summary

Will I have to stop taking my current medications?

The trial requires that participants do not use any regular medication or supplement that may affect appetite, energy balance, or sleep. If you are starting any new prescription medication, you must do so at least two weeks before the first study day visit and not during the study.

What evidence supports the effectiveness of the treatment exogenous ketones for obesity?

Research suggests that ketone supplements, like β-hydroxybutyrate (BHB), may help with weight management by increasing energy expenditure and improving body weight regulation. Additionally, BHB supplements have been shown to improve brain health and cognitive function in people with obesity, which could be beneficial for overall health. ^{1 2 3 4 5}

Is it safe for humans to use exogenous ketones?

A study with 24 healthy adults found that using a ketone monoester supplement for 28 days was safe and well-tolerated, with no significant changes in body weight, blood sugar, cholesterol, or kidney function. Mild nausea was reported in a few cases. ^{1 2 4 6 7}

How is the treatment of exogenous ketones for obesity different from other treatments?

Exogenous ketones, like ketone esters and salts, offer a unique approach to obesity by rapidly increasing blood ketone levels without the need for fasting or a strict ketogenic diet, potentially enhancing energy expenditure and weight regulation. This method is distinct from traditional weight loss strategies that often rely on calorie restriction or increased physical activity. ^{1 2 4 6 7}

What is the purpose of this trial?

People with obesity have different appetitive responses to stimuli compared to people without obesity. For example, people with obesity have a blunted postprandial ghrelin ('hunger' hormone) response, lower glucagon-like peptide 1 (GLP-1) and peptide-YY (PYY; associated with satiety) compared to people without obesity. Given the favorable effects of exogenous ketones on appetite previously observed in healthy adults of normal body weight, it is possible that these supplements can alter appetite hormones in a manner that may closer match that observed in people without obesity. To explore this research question, investigators will conduct a randomized single-blind cross over study to characterize appetite and dietary intake after ingestion of an exogenous ketone supplement within adults with obesity (compared a control condition without exogenous ketones) and compared to adults without obesity. The research team will also explore differences in postprandial energy expenditure and fuel utilization. Twenty-two healthy young- and middle-aged adults will be included (up to n=26 enrolled). In addition to a baseline visit to measure body composition, participants will undergo two 4.5-hour study visits, one of which will include a ketone diol supplement and one will have a placebo. Participants will be given a 1-day run-in diet prior to each study day to support energy balance. On each study day visit, participants will undergo a resting metabolic rate test (indirect calorimetry) followed by a fasting appetite rating and blood sample collection. Participants will then be provided with a standard breakfast meal (one with the ketone supplement and one with placebo). Appetite ratings and blood sample collection will be repeated 60, 120, and 180 minutes after the meal. Indirect calorimetry will be completed after the 30, 90, and 150 minute assessments. After the 180-minute timepoint, participants will be provided with a buffet-like lunch meal with instructions to eat as much or as little as they would like to determine ad libitum dietary intake at a single meal. To assess free-living ad libitum dietary intake, participants will receive 1.5 days of food boxes tailored to their preferences, with uneaten food returned at the end of the 1.5-day period. This study will be the first to assess the impact of exogenous ketones on appetite in obesity and would help inform future weight loss intervention trials.

Eligibility Criteria

This trial is for young and middle-aged adults with obesity who are healthy otherwise. They should be interested in how a ketone supplement might affect their appetite, energy use, and eating habits compared to a placebo. Participants will need to commit to several study visits and follow specific dietary instructions.

Inclusion Criteria

Not currently pregnant or lactating, not planning to become pregnant in the next 12 weeks

Body mass index (BMI): 18.5 - 40.0 kg/m2

Ability and willingness to fast for 12 hours before each study day visit

Exclusion Criteria

I have or had major health issues like heart disease, diabetes, cancer, thyroid problems, HIV, hepatitis B or C, kidney or liver diseases, or polycystic ovary syndrome.

I have untreated conditions like high blood pressure or sleep problems that could affect my appetite or energy.

Currently or in the past six months: use of regular medication or supplement that may affect appetite, energy balance, or sleep, regular use of tobacco or nicotine products, starting any new prescription medication within two weeks of the first study day visit or during the study, working night shifts or traveling across more than 2 time zones within two weeks of and throughout the study, food intolerances or allergies that cannot be accommodated, history of surgical procedure for weight loss at any time (e.g., gastroplasty, gastric bypass, gastrectomy or partial gastrectomy, adjustable banding, gastric sleeve); history of extensive bowel resection for other reasons, current alcohol or substance abuse (score >2 on the cut down-annoyed-guilty-eye opener [CAGE] questionnaire), current or past history of eating disorders including anorexia nervosa, bulimia, binge eating disorder (self-report or score >20 on the Eating Attitudes Test - 26 [EATS-26] questionnaire), weight loss >5% in past 12 weeks for any reason

Timeline

Screening and Baseline

Participants are screened for eligibility to participate in the trial

1 hour

1 visit (in-person)

Run-in Diet

Participants follow a 1-day energy-balanced run-in diet to ensure energy balance and weight maintenance prior to each study day

1 day

Study Visit Days

Participants undergo two 4.5-hour study visits, one with the exogenous ketone supplement and one with placebo, including metabolic rate tests, appetite ratings, and blood sample collections

4.5-5 hours per visit

2 visits (in-person)

Post-study Day Dietary Intake Assessment

Participants are provided with 1.5 days of meals and snacks to assess free-living ad libitum dietary intake

1.5 days

Follow-up

Participants are monitored for safety and effectiveness after treatment

1 week

Treatment Details

Interventions

• Exogenous Ketones

Trial Overview The study tests if exogenous ketones can change appetite hormones in obese individuals to resemble those without obesity. It's a randomized single-blind crossover study where participants take a ketone ester or placebo on different days, followed by measuring hunger ratings, hormone levels, energy expenditure, and food intake.

Participant Groups

Group I: Ketone supplement condition second Experimental Treatment 1 Intervention

Group II: Ketone supplement condition first Experimental Treatment 1 Intervention

Exogenous Ketones is already approved in United States, European Union for the following indications:

Approved in United States as Exogenous Ketones for:

• General Health and Wellness
• Appetite Suppression

Approved in European Union as Exogenous Ketones for:

• General Health and Wellness
• Appetite Suppression

Who Is Running the Clinical Trial?

University of British Columbia

Lead Sponsor

Trials

1,506

Recruited

2,528,000+

Findings from Research

A hypocaloric ketogenic diet (KD) significantly increased levels of beta-hydroxybutyrate (BHB) in participants, and this effect was enhanced by the addition of exogenous ketone salts (KS), leading to a 26% increase in ketonemia compared to a placebo.

The combination of the KD and KS not only augmented ketonemia but also resulted in a 6% reduction in fasting glucose levels, suggesting that the hypoglycemic effects of a ketogenic diet may be further improved with exogenous ketones.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Fasting and diurnal blood ketonemia and glycemia responses to a six-week, energy-controlled ketogenic diet, supplemented with racemic R/S-BHB salts. Buga, A., Kackley, ML., Crabtree, CD., et al.[2023]

A one-day ketogenic diet significantly increased total energy expenditure by about 110 calories compared to an isocaloric control diet, suggesting it may help with energy balance.

Supplementation with exogenous ketone salts did not enhance energy expenditure or appetite regulation compared to the isocaloric control diet, indicating that they may not provide additional benefits in energy balance.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Impact of one-day fasting, ketogenic diet or exogenous ketones on control of energy balance in healthy participants. Hägele, FA., Dörner, R., Koop, J., et al.[2023]

Ketone bodies, particularly β-hydroxybutyrate (BOHB) and acetone, can significantly increase in concentration during certain diseases or therapeutic interventions, providing valuable metabolic insights for managing conditions like heart failure and obesity-related diseases.

Monitoring ketone body levels can help optimize weight loss strategies and improve disease management by promoting the use of ketones as an alternative fuel source when glucose utilization is impaired.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Measuring ketone bodies for the monitoring of pathologic and therapeutic ketosis. Anderson, JC., Mattar, SG., Greenway, FL., et al.[2022]

In a randomized controlled trial with 18 adults with prediabetes, a ketone monoester (KEβHB) supplement significantly lowered plasma glucose levels compared to a placebo, indicating its potential for managing blood sugar in at-risk individuals.

The KEβHB supplement also increased levels of insulin and other glucoregulatory peptides, suggesting a mechanism by which it may help improve glucose control in prediabetes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Acute Nutritional Ketosis and Its Implications for Plasma Glucose and Glucoregulatory Peptides in Adults with Prediabetes: A Crossover Placebo-Controlled Randomized Trial. Bharmal, SH., Cho, J., Alarcon Ramos, GC., et al.[2023]

In a study involving 14 adults with obesity, 14 days of β-hydroxybutyrate (β-OHB) supplementation significantly improved cerebral blood flow and cognition, suggesting potential benefits for brain health in this population.

While β-OHB supplementation enhanced cognitive performance and cerebrovascular outcomes, it did not affect levels of brain-derived neurotrophic factor (BDNF), indicating that the cognitive improvements may be primarily due to increased blood flow rather than changes in BDNF levels.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Short-term ketone monoester supplementation improves cerebral blood flow and cognition in obesity: A randomized cross-over trial. Walsh, JJ., Caldwell, HG., Neudorf, H., et al.[2022]

A study involving 24 healthy adults showed that consuming a ketone monoester three times a day for 28 days safely elevated blood ketone levels without affecting body weight, blood glucose, cholesterol, or kidney function.

The only reported side effect was mild nausea in a small number of instances, indicating that the ketone monoester is well-tolerated for sustained use.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety and tolerability of sustained exogenous ketosis using ketone monoester drinks for 28 days in healthy adults. Soto-Mota, A., Vansant, H., Evans, RD., et al.[2020]

In a study involving 18 adults with prediabetes, ingestion of the ketone monoester β-hydroxybutyrate (KEβHB) significantly elevated blood ketone levels and resulted in lower levels of remnant cholesterol and triglycerides, indicating potential cardiovascular benefits.

The positive effects on lipid profile were more pronounced in individuals with higher habitual saturated fat intake, suggesting that KEβHB may be particularly beneficial for those at risk of cardiovascular disease.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effect of acute ketosis on lipid profile in prediabetes: findings from a cross-over randomized controlled trial. Liu, Y., Bharmal, SH., Kimita, W., et al.[2022]

References

1. England pubmed.ncbi.nlm.nih.gov

Fasting and diurnal blood ketonemia and glycemia responses to a six-week, energy-controlled ketogenic diet, supplemented with racemic R/S-BHB salts. [2023]

2. England pubmed.ncbi.nlm.nih.gov

Impact of one-day fasting, ketogenic diet or exogenous ketones on control of energy balance in healthy participants. [2023]

3. United States pubmed.ncbi.nlm.nih.gov

Measuring ketone bodies for the monitoring of pathologic and therapeutic ketosis. [2022]

4. United States pubmed.ncbi.nlm.nih.gov

Acute Nutritional Ketosis and Its Implications for Plasma Glucose and Glucoregulatory Peptides in Adults with Prediabetes: A Crossover Placebo-Controlled Randomized Trial. [2023]

5. England pubmed.ncbi.nlm.nih.gov

Short-term ketone monoester supplementation improves cerebral blood flow and cognition in obesity: A randomized cross-over trial. [2022]

6. Netherlands pubmed.ncbi.nlm.nih.gov

Safety and tolerability of sustained exogenous ketosis using ketone monoester drinks for 28 days in healthy adults. [2020]

7. England pubmed.ncbi.nlm.nih.gov

Effect of acute ketosis on lipid profile in prediabetes: findings from a cross-over randomized controlled trial. [2022]